TY - JOUR
T1 - Pivotal role of Cu,Zn-superoxide dismutase in endothelium-dependent hyperpolarization
AU - Morikawa, Keiko
AU - Shimokawa, Hiroaki
AU - Matoba, Tetsuya
AU - Kubota, Hiroshi
AU - Akaike, Takaaki
AU - Talukder, M. A.Hassan
AU - Hatanaka, Makoto
AU - Fujiki, Takako
AU - Maeda, Hiroshi
AU - Takahashi, Shosuke
AU - Takeshita, Akira
PY - 2003/12
Y1 - 2003/12
N2 - The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, NO, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived H2O 2 is an EDHF in mesenteric arteries of mice and humans and in porcine coronary microvessels. However, the mechanism for the endothelial production of H2O2 as an EDHF remains to be elucidated. In this study, we tested our hypothesis that Cu,Zn-superoxide dismutase (Cu,Zn-SOD) plays a pivotal role in endothelium-dependent hyperpolarization, using control and Cu,Zn-SOD-/- mice. In mesenteric arteries, EDHF-mediated relaxations and hyperpolarizations were significantly reduced in Cu,Zn-SOD-/- mice with no inhibitory effect of catalase, while endothelium-independent relaxations and hyperpolarizations were preserved. Endothelial H2O2 production also was significantly reduced in Cu,Zn-SOD-/- mice. In Langendorff isolated heart, bradykinin-induced increase in coronary flow was significantly reduced in Cu,Zn-SOD-/- mice, again with no inhibitory effect of catalase. The exogenous SOD mimetic tempol significantly improved EDHF-mediated relaxations and hyperpolarizations and coronary flow response in Cu,Zn-SOD-/- mice. These results prove the novel concept that endothelial Cu,Zn-SOD plays an important role as an "EDHF synthase" in mice, in addition to its classical role to scavenge superoxide anions.
AB - The endothelium plays an important role in maintaining vascular homeostasis by synthesizing and releasing several vasodilating factors, including prostacyclin, NO, and endothelium-derived hyperpolarizing factor (EDHF). We have recently identified that endothelium-derived H2O 2 is an EDHF in mesenteric arteries of mice and humans and in porcine coronary microvessels. However, the mechanism for the endothelial production of H2O2 as an EDHF remains to be elucidated. In this study, we tested our hypothesis that Cu,Zn-superoxide dismutase (Cu,Zn-SOD) plays a pivotal role in endothelium-dependent hyperpolarization, using control and Cu,Zn-SOD-/- mice. In mesenteric arteries, EDHF-mediated relaxations and hyperpolarizations were significantly reduced in Cu,Zn-SOD-/- mice with no inhibitory effect of catalase, while endothelium-independent relaxations and hyperpolarizations were preserved. Endothelial H2O2 production also was significantly reduced in Cu,Zn-SOD-/- mice. In Langendorff isolated heart, bradykinin-induced increase in coronary flow was significantly reduced in Cu,Zn-SOD-/- mice, again with no inhibitory effect of catalase. The exogenous SOD mimetic tempol significantly improved EDHF-mediated relaxations and hyperpolarizations and coronary flow response in Cu,Zn-SOD-/- mice. These results prove the novel concept that endothelial Cu,Zn-SOD plays an important role as an "EDHF synthase" in mice, in addition to its classical role to scavenge superoxide anions.
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U2 - 10.1172/JCI200319351
DO - 10.1172/JCI200319351
M3 - Article
C2 - 14679182
AN - SCOPUS:9144223017
SN - 0021-9738
VL - 112
SP - 1871
EP - 1879
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -